Method of fluorination

ABSTRACT

A method of fluorination comprising reacting monosaccharides, oligosaccharides, polysaccharides, composite saccharides formed by bonding of these saccharides with proteins and lipids and saccharides having polyalcohols, aldehydes, ketones and acids of the polyalcohols, and derivatives and condensates of these compounds with a fluorinating agent represented by general formula (I) thermally or under irradiation with microwave or an electromagnetic wave having a wavelength around the microwave region. In accordance with the method, the fluorination at a selected position can be conducted safely at a temperature in the range of 150 to 200° C. where the reaction is difficult in accordance with conventional methods. The above method comprising the irradiation with microwave or an electromagnetic wave having a wavelength around the microwave region can be applied to substrates other than saccharides. When a complex compound comprising HF and a base is reacted under irradiation with microwave, fluorination at a specific position which is difficult in accordance with conventional methods proceeds highly selectively, efficiently in a short time and safely.

TECHNICAL FIELD

The present invention relates to a method of fluorination. Moreparticularly, the present invention relates to a method of selectivelyfluorinating saccharides useful as the functional chemicals such asmaterials for drugs, cosmetics and healthy foods, and a method ofefficiently fluorinating a substrate by bringing the substrate intoreaction with a fluorinating agent under irradiation with microwave orelectromagnetic wave having a wavelength around the microwave region.

BACKGROUND ART

Compounds having fluorine have been attracting attention in variousfields such as the medical field and the field of electronic materialssince the unique property derived from fluorine atom leads to exhibitionof various useful functions, and the compounds have numerousapplications. Therefore, various methods of effectively introducingfluorine atom into substrates have been studied. Examples of the widelyknown methods include the method of direct fluorination described inJapanese Patent Application Laid-Open No. Showa 53(1978)-1827; theso-called method of halogen exchange described in Yuki Gosei Kagaku(Organic Synthetic Chemistry), volume 47, page 258 (1999), in which ahalogen atom in a compound having the halogen atom is exchanged withfluorine atom using HF or an alkali metal salt of fluorine such as KF;the method using hydrogen fluoride and a base such as pyridine andtriethylamine; the method using a hypervalent iodine such as IF₅; themethod using a specific fluorinating agent such as SF₄, DAST and afluoroalkylamine, examples of which include the Yarovenko reagent; andthe method of electrolytic fluorination (Chemistry of Organic FluorineCompounds II, Monograph, American Chemical Society, 1995, page 187).

However, among the conventional methods, the methods of fluorinationusing fluorine gas, SF₄ or DAST have a great problem with respect tosafety of the reaction. The method using a nucleophilic fluorinatingagent which can introduce fluorine atom conveniently and safely such asa combination of HF and a base is frequently conducted in early stagesof research and development since distillation is made possible byadjusting the number of the HF molecule coordinated to the base, andglass wares can be used without the possibility of corrosion. Thismethod is described in references (Journal fur practische ChemieChemiker-Zeitung, 338 (1996), pages 99 to 113; G. A. Olah, SyntheticFluorine Chemistry, chapter 8, 1992, John Wiley).

Examples of the method using a nucleophilic fluorinating agent includefluorination of sugars by the halogen-fluorine exchange such as thehalogen-fluorine exchange of a compound having a halogen atom activatedby carbonyl group at the α-position, the halogen-fluorine exchange oftrichloropyrimidine and the halogen-fluorine exchange of a sugartriflate; synthesis of fluoroethanols by ring-opening fluorination ofoxirane compounds (formation of a fluorohydrin); formation of halofluorogroup or fluorosulfenyl group in unsaturated compounds; synthesis offluorobenzene by fluorination accompanied with removal of diazo group;gem-difluorination of 1,3-dithiolanes and hydrazones; and the reactionof removing protective group of silyl ethers.

However, although the easy formation of free HF can be suppressed sothat the safety of the complex compound of HF and a base is enhanced,drawbacks arise in that the formation of the fluorine anion having thenucleophilicity becomes difficult, and the reactivity is small.Therefore, severe reaction conditions are necessary to obtain anexcellent result of the reaction, and it is often difficult that thedesired reaction proceeds. Moreover, from the standpoint of theindustrial application, improvement is necessary for completing thereaction at a low temperature in a short time so that the energy cost isreduced.

It is the actual situation that the other fluorinating agents areexpensive and cannot be handled easily. Among the above methods, themethod of using a specific compound having fluorine atom as thefluorinating agent is frequently used in the early stage of research anddevelopment on drugs and functional materials since fluorine atom can beintroduced relatively easily. However, as described above, theconventional technology of fluorination is not satisfactory for makingthe desired fluorination proceed selectively, efficiently and safely.

Recently, various attempts have been made to improve the selectivity andthe activity of the reaction. Examples of the attempt include theacceleration of the reaction using microwave. Since microwave does nothave energy sufficient for starting a reaction, the application ofmicrowave to chemical reactions is heretofore rarely conducted.Recently, a study showing that the activity and the selectivity of areaction is improved by irradiation with microwave has been reported.This report is attracting attention since the result cannot be explainedby the simple acceleration of the reaction by heating (Journal ofPhysical Organic Chemistry, 2000 (13), 579-586). However, the attemptson the application of microwave to the fluorination are scarce. Forexample, no reports can be found except the application to the Schiemanreaction (Japanese Patent Application (as a national phase under PCT)Laid-Open No. Heisei 12(2000)-59384).

As for saccharides, a wide range of application and development areexpected since saccharides play important roles in the activities of thelife such as the communication between cells and the mechanism ofimmunity as the energy source and as the sugar chain in proteins andhave the ability of forming organs such as skins and bones. For example,chitosan, which is a high order condensate having a repeating unit ofglucosamine and is produced by hydrolysis or fermentation of crustaceansor glucose as the material, is used as an additive, an antiseptic or apet food in the field of foods and as an artificial skin, a stitchingthread, a membrane for artificial dialysis and a film for controlledrelease in the field of medical treatments. Chitosan is also used in thefield of the drug as an anticancer agent, an immunostimulator, an agentfor suppressing blood glucose elevation and an agent for suppressingcholesterol absorption, in the field of the agriculture as an agent forsoil amelioration, an antivirus agent and an insecticide, in the fieldof industry as soap, a hair tonic, a cosmetic and a tooth paste, and inthe field of the environment as an agent for trapping waste fluids andan agent for treating heavy metals and waste water.

As described above, as the application of saccharides, the developmentof products having useful functions in the fields of foods, drugs,medical treatments, agriculture, industry and environment is promoted bybonding specific monosaccharides in higher orders or by introducingamino group, acetyl group or fluorine atom into saccharides.

In particular, fluorinated sugars obtained by fluorinating saccharidesexhibiting excellent adaptability to the human body are actively studiedfor application as the anticancer agent and an immunosuppressant.Examples of the method of fluorination used for this purpose include thedirect fluorination with the fluorine gas, the method ofhalogen-fluorine exchange, the method using hydrogen fluoride and a basesuch as pyridine and triethylamine, and the method using a fluorinatingagent such as IF₅, SF₄, DAST and the Yarovenko reagent.

However, the introduction of fluorine atom into a specific position of asaccharide is often difficult since a saccharide has a plurality ofactive groups such as hydroxyl groups. For example, it is known that,when methyl 2,3-0-isopropylidene-β-D-ribofuranoside is fluorinated withDAST, 2,3-0-isopropylidene-5-0-methyl-β-D-ribofuranosyl fluoride whichis a product of rearrangement is obtained, but the fluorination ofhydroxyl group as the object reaction does not proceed. It is also knownthat the object reaction does not proceed when the combination of HF anda base which is a convenient fluorinating agent such as the HF-pyridinecomplex compound and the HF-triethylamine complex compound is used. Whenan agent having a greater acidity is used to promote the reaction, sidereactions such as scission of the protective group take place.

When fluorine gas having a greater reactivity is used, the selectiveintroduction of fluorine is impossible. To obtain the object compound,it is necessary that the halogenation be conducted using another halogenhaving a smaller reactivity, and then the halogen-fluorine exchange beconducted.

As described above, it is very difficult that a specific position of asaccharide is easily fluorinated without affecting the protective groupin accordance with the conventional technology.

The present invention has an object of overcoming the above problems andproviding a method of making the fluorination of a desired substrateproceed highly selectively, efficiently and safely, and to provide amethod of fluorinating a specific position of a saccharide selectivelywithout affecting a protective group at a temperature within a widerange safely and easily.

DISCLOSURE OF THE INVENTION

As the result of intensive studies by the present inventors to overcomethe above problems, it was found that, when monosaccharides,oligosaccharides, polysaccharides, composite saccharides formed bybonding of these saccharides with proteins and lipids and saccharideshaving polyalcohols, aldehydes, ketones and acids of the polyalcohols,and derivatives and condensates of these compounds were brought intoreaction with a specific fluorinating agent thermally or underirradiation with microwave or an electromagnetic wave having awavelength around the microwave region, the fluorination could beconducted selectively at a specific position safely at a temperature inthe range of 150 to 200° C. where the reaction was heretofore difficult.

It was also found by the present inventors that the method ofirradiating with microwave or electromagnetic wave having a wavelengtharound the microwave region could be applied to substrates other thanthe saccharides, and the fluorination at a specific position which hadbeen difficult in accordance with the conventional technology proceededhighly selectively, efficiently in a short time and safely by conductingthe reaction using other fluorinating agents under irradiation withmicrowave.

The present invention provides:

-   (1) A method of fluorination which comprises fluorinating a    saccharide using a fluorinating agent represented by general formula    (I):    wherein Y represents nitrogen atom or phosphorus atom, R⁰, R¹ and R²    represent hydrogen atom or an alkyl or aryl group which may have    substituents, the atom and the groups represented by R⁰, R¹ and R²    may be a same with or different from each other, and two or three of    the groups represented by R⁰, R¹ and R² may be bonded to each other    to form a ring;-   (2) A method of fluorination described above in (1), wherein, in    general formula (I), Y represents nitrogen atom, R⁰ represents    3-methylphenyl group or 2-methoxyphenyl group, and R¹ and R²    represent ethyl group;-   (3) A method of fluorination described above in any one of (1) and    (2), wherein the saccharide is fluorinated by a thermal reaction;-   (4) A method of fluorination which comprises fluorinating a    substrate by bringing the substrate and a fluorinating agent into    reaction with each other under irradiation with at least one of    microwave and electromagnetic wave having a wavelength around a    microwave region.-   (5) A method of fluorination described above in (4), wherein the    fluorinating agent is a compound represented by general formula    (II):    wherein Y represents nitrogen atom or phosphorus atom, X represents    hydrogen atom or a halogen atom, R⁰, R¹ and R² represent hydrogen    atom or an alkyl or aryl group which may have substituents, the atom    and the groups represented by R⁰, R¹ and R² may be a same with or    different from each other, and two or three of the groups    represented by R⁰, R¹ and R² may be bonded to each other to form a    ring;-   (6) A method of fluorination described above in (5), wherein the    fluorinating agent is a compound represented by general formula    (III):    wherein R³, R⁴ and R⁵ each independently represent an alkyl or aryl    group which may have substituents, X represents hydrogen atom or a    halogen atom, and two or three of the groups represented by R³, R⁴    and R⁵ may be bonded to each other to form a cyclic structure;-   (7) A method of fluorination described above in any one of (5) and    (6), wherein the substrate is an organic compound having at least    one atom selected from oxygen atom, nitrogen atom and sulfur atom;-   (8) A method of fluorination described above in (4), wherein the    fluorinating agent is a complex compound comprising HF and a base;    and-   (9) A method of fluorination described above in (8), wherein the    substrate is a compound having hydrogen atom activated by a    substituent at an α position, a β-position or a γ-position, a silyl    ether compound, a compound having an unsaturated group, hydroxyl    group, a halogeno group, amino group, diazo group, triazeno group or    isocyano group as a functional group, or a cyclic compound having    three-membered or greater ring which may have heteroatoms.

THE MOST PREFERRED EMBODIMENT TO CARRY OUT THE INVENTION

As the saccharide used in the present invention, polyalcohols and othersubstances can be used. Examples of the other substances includemonosaccharides such as glucose, fucose, N-acetylglucosamine,N-acetylgalactosamine, N-acetylneuraminic acid, erythrose, threose,ribose, arabinose, xylose, arose, lyxose, altrose, mannose, gulose,idose, galactose, talose, psicose, furctose, sorbose, tagatose,unsaturated sugars having an unsaturated bond such as hexaenose,branched sugars such as apiose, and derivative of sugars such as deoxysugars, amino sugars, thio sugars, condensed sugars and anhydrides ofmonosaccharides; oligosaccharides, including disaccharides, comprisingtwo to several monosaccharides bonded through the glycoside bond such asmaltose, cane sugar and lactose; polysaccharides such as starch,glycogen and cellulose; composite saccharides obtained by bonding ofthese saccharides with proteins and lipids; and nucleosides,oligonucleosides, ribonucleic acid and deoxyribonucleic acid which areobtained by bonding of these saccharides with bases of nucleic acids.

The fluorinating agent used for fluorination of the above saccharides isa compound represented by the following general formula (I):

In general formula (I), R⁰, R¹ and R² represent hydrogen atom or analkyl or aryl group which may have substituents, the atom and the groupsrepresented by R⁰, R¹ and R² may be the same with or different from eachother, and two or three of the groups represented by R⁰, R¹ and R² maybe bonded to each other to form a ring.

As the alkyl group, saturated and unsaturated aliphatic and alicyclicalkyl groups having 1 to 32 carbon atoms are preferable. Examples of thealkyl group include methyl group, ethyl group, propyl group, isopropylgroup, butyl group, isobutyl group, t-butyl group, pentyl group, hexylgroup, heptyl group, octyl group, 2-ethylhexyl group, nonyl group, decylgroup, cyclohexyl group, cyclooctyl group, decalyl group, norbornylgroup, bicyclohexyl group, adamantyl group, isomers of these groups,hydroxymethyl group, hydroxyethyl group, hydroxypropyl group andhydroxybutyl group.

Examples of the aryl group include aromatic aryl groups such as phenylgroup, o-tolyl group, m-tolyl group, p-tolyl group, o-xylyl group,m-xylyl group, p-xylyl group, dimethylphenyl group, isomers ofdimethylphenyl group having methyl group at different positions, cumylgroup, mesityl group, trimethylphenyl group, hydroxyphenyl group,methoxyphenyl group, isomers of methoxyphenyl group having methoxylgroup at different positions, naphthyl group, methylnaphthyl group,dimethylnaphthyl group, hydroxynaphthyl group, biphenyl group, tetralylgroup, terphenyl group, anthryl group, benzothienyl group, chromenylgroup, indolyl group, pyridyl group and quinolyl group; and groupshaving heterocyclic rings.

The alkyl group and the aryl group may have other functional groups suchas hydroxyl group, halogen groups, nitro group, mercapto group, aminogroup, amide group, cyano group, carbonyl group, carboxyl group, acetylgroup, acyl group, alkoxyl groups and sulfone group.

Among the fluorinating agents represented by general formula (I),compounds represented by general formula (I) in which Y representsnitrogen atom, R⁰ represents 3-methylphenyl group or 2-methoxyphenylgroup, and R¹ and R² represent ethyl group are preferable. Among thesecompounds, N,N-diethyl-α,α-difluoro(3-methyl)benzylamine andN,N-diethyl-α,α-difluoro(2-methoxy)benzylamine, which are compoundsrepresented by general formula (I) in which R⁰ represents 3-methylphenylgroup or 2-methoxyphenyl group, and R¹ and R² represent ethyl group, aremore preferable since the compounds exhibit the excellent heat stabilitysuch that the compounds are stable at a high temperature of 150° C. orhigher.

It is preferable that the fluorinating agent represented by generalformula (I) is used in an amount of 1 mole or more per 1 mole of thefunctional group in the substrate taking part in the reaction. Thereaction may be allowed to proceed while the fluorinating agent is usedin an excess amount or in an amount less than the stoichiometry.

The fluorination can be conducted in accordance with a batch process, asemi-batch process or a continuous process. The fluorination can beconducted in accordance with the conventional thermal reaction or underirradiation with microwave and/or electromagnetic wave having awavelength around the microwave region.

The reaction can be safely performed when the temperature of thereaction is lower than the so-called runaway temperature under heating(the temperature at which the heat generation starts in the ARC test).It is preferable that the fluorination is conducted at 200° C. or lowerand more preferably at a temperature in the range of the roomtemperature to 150° C. When the thermal reaction is conducted, thefluorination is conducted at a temperature lower than the runawaytemperature under heating.

When the fluorination is conducted under irradiation with microwave orelectromagnetic wave having a wavelength around the microwave region, ingeneral, it is preferable that microwave having a frequency of 1 to 30GHz is used. Electromagnetic wave having a frequency outside the aboverange such as millimeter wave having a frequency greater than 30 GHz and300 GHz or smaller and electromagnetic wave having a frequency in therange of 0.3 GHz or greater and smaller than 1 GHz can also be used. Theelectromagnetic wave can be applied continuously or intermittently whilethe temperature is adjusted. For example, a conventional reactor forbatch reactions is covered with a shield so that the microwave does notleak, and microwave is applied to the reactor. For this purpose, acommercial microwave oven is advantageously used, and a commercial ovenfor chemical synthesis may be used. The output of the magnetron tube forgeneration of microwave used for the reaction and the intensity of theirradiation are not particularly limited except the legal restrictions.An easily available tube having an output of 200 to 6,000 W ispreferable. A plurality of tubes may be used in combination when agreater output is necessary. It is preferable that the intensity of theirradiation with microwave is, in general, 20 W/cm² or greater and morepreferably 100 W/cm² or greater.

It is preferable that the time of the reaction is in the range of 10 to360 minutes when the thermal reaction is conducted. When the reaction isconducted under irradiation of microwave and/or electromagnetic wavehaving a wavelength around the microwave region, in general, the time ofthe reaction is shorter than that in the thermal reaction. It ispreferable that the time of the irradiation is 0.1 to 200 minutes, morepreferably 0.1 to 60 minutes and most preferably 1 to 30 minutesalthough the time of the irradiation is different depending on the typeof the substrate. In a pretreatment such as drying and in thefluorination, microwave may be applied for 3 hours or longer, wherenecessary. As for the temperature of the reaction, the reaction may beconducted at a temperature in a range such that the substrate, thefluorinating agent and the reaction products are stable. In general, atemperature in the range of the room temperature of about 25° C. to 200°C. is preferable. However, the reaction may be conducted at atemperature lower than the room temperature or higher than 200° C.

For making the fluorination proceed, it is not necessary that a solventis used. A solvent may be used for conducting the stirring sufficientlyor preventing elevation of the temperature. Examples of the preferablesolvent include aliphatic hydrocarbons, aromatic hydrocarbons,halogenated hydrocarbons, aromatic halogenated hydrocarbons, nitritesand ethers which are inter to the substrate, the fluorinating agent andthe reaction products. A suitable combination of the solvents may beused.

When the irradiation with microwave is completed, the reaction productmay be separated after treatments such as post treatments, extraction,distillation and filtration similarly to the treatments in the ordinarythermal reaction.

When the reaction is conducted using the fluorinating agent representedby general formula (I) exhibiting the excellent heat stability inaccordance with the thermal reaction or under irradiation with microwaveand/or electromagnetic wave having a wavelength around the microwaveregion, a specific portion of a saccharide can be fluorinatedselectively and easily without affecting the protective group in thewide range of the temperature which is difficult in conventionalreactions.

The above method of fluorination comprising conducting the reactionunder irradiation with microwave and/or electromagnetic wave having awavelength around the microwave region can be applied to fluorination ofsubstrates other than saccharides using a fluorinating agent other thanthe fluorinating agent represented by general formula (I).

For example, in the method of fluorination under irradiation withmicrowave and/or electromagnetic wave having a wavelength around themicrowave region, a fluorinating agent represented by general formula(II):

may be used.

In general formula (II), X represents hydrogen atom or a halogen atom,and R⁰, R¹ and R² and Y are as defined for general formula (I).

As the preferable fluorinating agent, a fluorinating agent representedby general formula (III):

can also be used.

In general formula (III), R³, R⁴ and R⁵ each independently represent analkyl or aryl group which may have substituents, and two or three of thegroups represented by R³, R⁴ and R⁵ may be bonded to each other to forma ring structure. Examples of the alkyl group and the aryl grouprepresented by R³, R⁴ and R⁵ include the groups described as theexamples of the alkyl groups and the aryl groups represented by R⁰, R¹and R³ in general formula (I).

In general formula (III), X represents hydrogen atom or a halogen atomsuch as fluorine atom, chlorine atom, bromine atom and iodine atom.

It is preferable that, in general formula (III) representing thefluorinating agent, R³ represents an aryl group which may havesubstituents, X represents fluorine atom, and R⁴ and R⁵ represent analkyl group or aryl group having 1 to 32 carbon atoms which may havesubstituents.

Examples of the compound represented by general formula (III) includealkylfluoroamines and arylfluoroamines. Examples of the compoundrepresented by general formula (III) in which R⁴ and R⁵ represent ethylgroup include N,N-diethyl-α,α-difluorobenzylamine,N,N-diethyl-α,α-difluoro(2-methyl)benzylamine,N,N-diethyl-α,α-difluoro-(3-methyl)benzylamine,N,N-diethyl-α,α-difluoro(4-methyl)benzylamine,N,N-diethyl-α,α-difluoro(2-methoxy)benzylamine,N,N-diethyl-α,α-difluoro(4-phenyl)benzylamine,N,N-diethyl-α,α-difluorocylcohexylmethylamine,N,N-diethyl-α,α-difluoropyridylmethylamine andN,N-diethyl-α,α-difluorocyclohexylmethylamine.

Among the compounds represented by general formula (III), aromaticfluoroamines such as N,N-diethyl-α,α-difluoro(3-methyl)-benzylamine,N,N-diisopropyl-α,α-difluoro(3-methyl)benzylamine,N,N-diethyl-α,α-difluoro(2-methoxy)benzylamine,N,N-diisopropyl-α,α-difluoro-(2-methoxy)benzylamine andN,N-di-n-butyl-α,α-difluoro(2-methoxy)-benzylamine are preferable due tothe excellent heat stability.

The substrates which can be fluorinated with the fluorinating agentrepresented by general formula (III) are organic compounds, polymers andinorganic compounds. The substrates are so numerous that it is difficultthat examples corresponding to the entire substrates are shown. Ingeneral, the substrate is an organic compound having oxygen atom,nitrogen atom or sulfur atom. Examples of the organic compound includeprimary, secondary and tertiary alcohols having isolated hydroxyl groupsas the functional groups; polyols having a plurality of hydroxyl groupssuch as 1,2-diols having adjacent hydroxyl groups, 1,3-diols and otherpolyols; thiols; compounds having carbonyl group or carboxyl group suchas aldehydes, ketones, carboxylic acids, hydroxycarboxylic acid, estersof carboxylic acids and lactones; aromatic compounds exhibiting anincreased nucleophilicity due to the presence of an electron-attractinggroup such as cyanohydrins, sulfonic acids, esters of sulfonic acids,thiocarboxylic acids, esters of thiocarboxylic acids anddinitrobenzenes; aromatic diazonium salts; heterocyclic compounds;saccharides such as monosaccharides, glycoxides, anhydrides ofmonosaccharides, oligosaccharides and polysaccharides; hydrocarbonshaving a cage shape such as fullerenes; and epoxides such as ethyleneoxide and epichlorohydrin. Specific examples of the substrate includeethanol, propyl alcohol, butyl alcohol, heptanol, octanol, benzylalcohol, phenetyl alcohol, nitrophenol, cyclohexanol, adamantanol,cholesterol, epiandrostrone, ethylene glycol, cyclohexanediol, glycerol,propylene oxide, alkyloxiranes, benzaldehyde, alkylbenzaldehydes,acetophenone, benzophenone, cyclopentanone, cyclohexanone, indanone,mandelonitrile, γ-butyrolactone, mevalonolactone, benzenesulfonic acid,naphthalene-sulfonic acid, thiobenzoic acid, methyl thiobenzoate,dinitrochlorobenzene, α-glucopyranose, β-D-fructofuranose,α-D-xylohexopyranose-4-urose, β-D-glucobinalronic acid and fullerenol.Examples of the specific compound providing a greater added valueinclude 2-hydroxymethyl-saccharine as the raw material of2-saccharinylmethylarylcarboxylates useful as the inhibitor forproteolysis enzymes, 2,3-di(4-pyridyl)-4-methylthiophene-3-carboaldehydeas an intermediate for pyridylthiophene used for curing diseasesoccurring via cytokine, dinucleotides and oligonucleotides used as thedrug for curing diseases caused by viruses such as herpes, and7β-carboxymethyl-4-aza-5α-cholestanone used as a raw material for theinhibitor for 5α-reductase.

Of course, the substrate used for fluorination using the fluorinatingagent represented by general formula (III) is not limited to thecompounds shown as the examples. Among the substrates, compounds havinghydroxyl group, saccharides, compounds having carbonyl group or carboxylgroup and epoxides are preferable. Among the compounds having hydroxylgroup, compounds having adjacent hydroxyl groups are more preferable.

The procedures for fluorination using the fluorinating agent representedby general formula (III) under irradiation with microwave and/orelectromagnetic wave having a wavelength around the microwave region areapproximately the same as those for fluorination using the fluorinatingagent represented by general formula (I) under irradiation withmicrowave and/or electromagnetic wave having a wavelength around themicrowave region. The temperature of the reaction can be selected in arange such that the substrate, the fluorinating agent and the reactionproducts are stable. In general, a temperature in the range of the roomtemperature of about 25° C. to 200° C. is preferable. However, thereaction may be conducted at a temperature lower than the roomtemperature or higher than 200° C.

When the fluorinating agent represented by general formula (I) in whichY represents nitrogen atom or when the fluorinating agent represented bygeneral formula (III) is used, the fluorinating agent can be recoveredas the corresponding amide after the fluorination has been completed,and a process for fluorination allowing recycling of the materials canbe constructed easily.

In accordance with the method of fluorination using the fluorinatingagent represented by general formula (III) under irradiation withmicrowave and/or electromagnetic wave having a wavelength around themicrowave region, the above substrate can be fluorinated efficiently ina short time safely with the excellent selectivity.

The method of fluorination under irradiation with microwave and/orelectromagnetic wave having a wavelength around the microwave region canbe applied to fluorination using a complex compound comprising HF and abase as the fluorinating agent.

Examples of the complex compound comprising HF and a base used as thefluorinating agent include alkylamine-HF complex compounds, melamine-HFcomplex compounds and pyridine-HF complex compounds. Among these complexcompounds, the triethylamine-nHF complex compounds (in general, nrepresents an integer) are preferable, and the triethylamine-3HF complexcompound is more preferable due to the easiness of handling since thecompound can be distilled and glass vessels can be used due to theabsence of the corrosive property.

When the complex compound of HF and a base is used as the fluorinatingagent, an agent accelerating the reaction may be used in combinationwith the fluorinating agent to accelerate the reaction. As the agentaccelerating the reaction, NBS (N-bromosuccinimide), DBH(1,3-dibromo-5,5-dimethylhidantoin) and sulfur chloride are used for thegem-difluorination of 1,3-dithiane, and sulfuryl compounds are used incombination with the complex compound of HF and a base for obtaininghalofluorides or fluorosulfenyl compounds from olefins and alkynes.

Examples of the substrate used in the method of fluorination using thecomplex compound of HF and a base as the fluorinating agent underirradiation with microwave and/or electromagnetic wave having awavelength around the microwave region include compounds having hydrogenatom activated by a substituent at the a position, the Deposition or theγ-position, silyl ether compounds, compounds having an unsaturatedgroup, hydroxyl group, a halogeno group, amino group, diazo group,triazeno group or isocyano group as the functional group, and cycliccompounds having three-membered or greater ring which may haveheteroatoms.

The above substrates are compounds which can take part in reactions suchas conversion of functional groups into fluorine, ring-openingfluorination of cyclic compounds, gem-difluorination of 1,3-dithiolaneand hydrazone, gem-trifluorination of ortho-thioesters, oxidativefluorination, reductive fluorination and reaction of removing theprotective group of silyl ethers. Examples of the conversion offunctional groups into fluorine include the halogen-fluorine exchangewith halogen compounds, formation of halofluorides, fluorosulfenylcompounds and nitrofluoro compounds from unsaturated groups in olefinsand alkynes, fluorination of hydroxyl groups in alcohols and saccharidesand fluorination of amino group, diazo group, triazeno group andisocyano group with removal of diazo group.

Specific examples of the above substrate include cyclic compounds whichmay have heteroatoms such as cyclopropane, cyclobutane, cyclopentane,cyclobutene, cylopentene, cyclohexene, cycloheptene, cyclooctene,cyclodecene, cyclododecene, butene, 2,3-dimethylbutene,methylenecyclohexene, 5-α-cholest-2-ene, ethylene oxide, propyleneoxide, oxetane, oxorane, cyclohexene oxide, cyclooctene oxide,cyclodecene oxide, cyclododecene oxide, alkyloxiranes, styrene oxide,norbornene oxide, aziridine, azirine, thiirane, azethidine, azolidine,thiazolidine, 1,3-dithiane; aromatic compounds, aromatic diazonium saltsand heterocyclic compounds exhibiting increased nucleophilicity due tothe presence of an electron-attracting group such as indanone,cyclopentanone, γ-butyrolactone, mevalonolacotne, bromoacetone,benzenesulfonic acid, naphthalenesulfonic acid, thiobenzoic acid, methylthiobenzoate, acrylic acid, methyl acrylate, methacrylic acid, methylmethacrylate and trichloropyrimidine; alcohols having hydroxyl group asthe functional group and sugars such as monosaccharides,oligosaccharides and polysaccharides, examples of which include allylalcohol, allyl veratrol, citroneral, α-D-glucopyranose,β-D-fructofuranose, α-D-xylohexopyranose-4-urose and β-D-glucobinalronicacid; compounds having unsaturated bonds such as propylene, butene,tolan and acetylenes; and hydrocarbons having a cage shape such asfullerenes. The above compounds may further have a plurality of otherfunctional groups.

Examples of the other functional group include a single or a pluralityof hydroxyl groups, thiol groups, formyl groups, carbonyl groups,carbonyloxyl groups, alkyloxycarbonyl groups, cyano groups, sulfonylgroups, alkylsulfonyl groups, sulfenyl groups, thiocarbonyl groups,nitro groups, amino groups and diazo groups, which may be primary,secondary or tertiary groups. The above method can be applied not onlyto organic compounds, but also to inorganic compounds, materialsobtained by introducing the functional group on the surface of polymersand organic-inorganic hybrid materials obtained by introducing thefunctional group.

Of course, the substrate used for fluorination using the complexcompound of HF and a base under irradiation with microwave and/orelectromagnetic wave having a wavelength around the microwave region isnot limited to the compounds shown as the examples. In the presentmethod, saccharides and cyclic compounds having cyclopropane ring,oxirane ring, aziridine ring, azirine ring or 1,3-dithiane ring arepreferable among these substrates.

The procedures for fluorination using the complex compound of HF and abase under irradiation with microwave and/or electromagnetic wave havinga wavelength around the microwave region are approximately the same asthose for fluorination using the fluorinating agent represented bygeneral formula (I). The temperature of the reaction can be selected ina range such that the substrate, the fluorinating agent and the reactionproducts are stable. In general, a temperature in the range of the roomtemperature of about 25° C. to 300° C. is preferable. However, thereaction may be conducted while the temperature is controlled at a valuelower than the room temperature or higher than 200° C. similarly to theordinary thermal reaction.

When the complex compound of HF and a base is used as the fluorinatingagent under irradiation with microwave and/or electromagnetic wavehaving a wavelength around the microwave region, the complex compound ofHF and a base which is stable and causes practically no corrosion, suchas the triethylamine-HF complex, can be used in various types offluorination for various substrates, and the fluorinationi can beconducted efficiently in a short time under a milder condition than thatof the thermal reaction. Examples of the above fluorination include thering-opening fluorination of compounds having hydrogen atom activated bya substituent at the a position, the β-position or the γ-position, silylether compounds, compounds having an unsaturated group, hydroxyl group,a halogeno group, amino group or diazonium group as the functionalgroup, and cyclic compounds having three-membered or greater ring whichmay have heteroatoms, formation of halofluorides or fluorosulfenylcompounds from unsaturated compounds, the halogen-fluorine exchange,fluorination with removal of diazo group, gem-difluorination of1,3-dithioranes and hydrazones and the removal of the protective groupof silyl ethers.

The present invention will be described more specifically with referenceto examples in the following. However, the present invention is notlimited to the examples.

A. Using the Fluorinating Agent Represented by General Formula (I)

<Synthesis of the Fluorinating Agent>

a) N,N-Diethyl-α-chloro-meta-toluylamidium chloride

Into a three-necked flask (300 ml), a solution of carbon tetrachloride(125 g) containing oxalyl chloride (25 g; 0.197 moles) was placed underthe atmosphere of nitrogen. While the flask was cooled with ice waterand the solution was stirred, N,N-diethyl-meta-toluamide (45 g; 0.236moles; referred to as DEET, hereinafter) was added dropwise over 20minutes. After the addition was completed, the resultant mixture waskept at the same temperature for 10 minutes. After the temperature ofthe content was adjusted at 50° C., the reaction was allowed to proceedfor 1 hour. Generation of a gas was observed during the reaction, andthen white precipitates were formed. The formed white precipitates wereseparated by filtration, washed with carbon tetrachloride and n-hexaneand dried, and N,N-diethyl-α-chloro-meta-toluylamidium chloride wasobtained. The obtained N,N-diethyl-α-chloro-meta-toluylamidium chloridewas heated slowly in a capillary tube (a sealed tube) to 200° C. Nodecomposition was observed, and the compound was thermally stable.

It was found that the obtained N,N-diethyl-α-chloro-meta-toluylamidiumchloride had a melting point of 54.6° C. in accordance with the thermalanalysis using TG-DTA.

b) N,N-Diethyl-α,α-difluoro(3-methyl)benzylamine

Into a three-necked flask (500 ml),N,N-diethyl-α-chloro-meta-toluylamidium chloride (25 g; 0.1 mole)prepared above, a spray dried product of potassium fluoride(manufactured by MORITA KAGAKU Co., Ltd.; 23.5 g; 0.4 moles) andacetonitrile (250 g) were placed, and the reaction was allowed toproceed at the reflux temperature of acetonitrile for 18 hours under theatmosphere of nitrogen. After the reaction was completed, the reactionmixture was cooled to the room temperature and filtered, and anacetonitrile solution containing a product of fluorine exchange withN,N-diethylchloro-meta-toluylamidium chloride was obtained. The obtainedsolution was distilled using a rectifier of the rotating band typehaving a theoretical number of stage of 80, and 13 g ofN,N-diethyl-α,α-difluoro(3-methyl)benzylamine (referred to as DEET-F,hereinafter) was obtained as a fraction at a temperature of 50 to 60° C.(the pressure: 2 mmHg, 260 Pa). The yield after the isolation bydistillation was about 60% based on the amount ofN,N-diethylchloro-meta-toluylamidium chloride.

The obtained fraction was a colorless transparent liquid and had thefollowing properties.

(Heat Stability and the Runaway Temperature Under Heating)

A sample of the product was slowly heated in a capillary tube (a sealedtube) to 200° C. and kept at this temperature for 1 hour. Nodecomposition was observed, and the product was thermally stable. In thethermal analysis in which the temperature was raised to 400° C. at arate of 10° C. per minute using an apparatus for the TG/DTA thermalanalysis, heat generation started at 210° C., and a gradual decrease inthe weight was observed. The peak temperature of the heat generation was280° C. The temperature of the start of heat generation was 180° C. asmeasured in accordance with the method of measuring the runaway reactionof Japanese Industrial Standard (the ARC test) for evaluating the heatstability of a substance in the adiabatic condition.

(Content of Fluorine)

Calculated: 17.8% by weight; found: 17.6% by weight.

c) N,N-Diethyl-2-methoxybenzamide

Into a three-necked flask (200 ml), a toluene solution (56 g) containingdiethylamine (25.80 g; 0.352 moles) was placed. While the flask wascooled with ice water and the solution was stirred, a toluene solution(30 g) of 2-methoxybenzoyl chloride (2.00 g; 0.117 moles) was addeddropwise over 30 minutes. After the addition was completed, water wasadded to the resultant mixture, and diethylamine and diethylaminehydrochloride in excess amounts were removed. The obtained toluene layerwas dehydrated with MgSO₄. Then, the solvent was removed bydistillation, and a light yellow liquid was obtained (the obtainedamount: 22.81 g; the yield: 94%).

d) Synthesis of N,N-diethyl-α-chloro(2-methoxyphenyl)amidium chloride

Into a three-necked flask (200 ml), a solution of carbon tetrachloride(54 g) containing oxalyl chloride (24.50 g; 0.193 mole) was placed underthe atmosphere of nitrogen. To the resultant mixture,N,N-diethyl-2-methoxybenzamide (20.05 g; 0.0965 moles) was addeddropwise over 20 minutes at the room temperature. After the addition wascompleted, the temperature of the content was adjusted at 50° C., andthe reaction was allowed to proceed for 5 hours. Generation of a gas wasobserved during the reaction, and then the reaction mixture wasseparated into two layers. After the reaction was completed, the solventwas removed by distillation. When the resultant product was leftstanding, a charcoal brown solid was obtained. The obtained solid waswashed with carbon tetrachloride and n-hexane and dried, andN,N-diethyl-α-chloro(2-methoxyphenyl)amidium chloride was obtained (theobtained amount: 21.40 g; the yield: 80%).

To confirm the ability of chlorination of the obtainedN,N-diethyl-α-chloro(2-methoxyphenyl)amidium chloride, the reaction withbenzyl alcohol was conducted in a glove box. Into a test tube,N,N-diethyl-α-chloro(2-methoxyphenyl)amidium chloride (0.20 g; 0.465moles), benzyl alcohol (0.11 g; 1.017 moles) and acetonitrile (1.10 g)were placed, and the reaction was allowed to proceed at the roomtemperature for 4 hours. As the result of analysis of the reaction fluidin accordance with GC, the formation of benzyl chloride was confirmed.

e) N,N-Diethyl-α,α-difluoro(2-methoxy)benzylamine

In a glove box, N,N-diethyl-α-chloro(2-methoxyphenyl)amidium chlorideprepared above (20.00 g; 0.0725 moles), potassium fluoride (manufacturedby MORITA KAGAKU SPRAY DRY Co., Ltd.; 17.72 g; 0.3052 moles) andacetonitrile (200 g) were placed into a three-necked flask (100 ml).Under the atmosphere of nitrogen, a condenser and an electromagneticstirrer were attached to the flask, and the reaction was allowed toproceed at 80° C. for 20 hours. After the reaction was completed, thereaction mixture was cooled to the room temperature and filtered in theglove box, and an acetonitrile solution containing a product of fluorineexchange with N,N-diethyl-α-chloro(2-methoxyphenyl)amidium chloride wasobtained.

This solution was distilled using a rectifier of the rotating band typehaving a theoretical number of stage of 80, andN,N-diethyl-α,α-difluoro(2-methoxy)benzylamine (9.86 g; the yield: 55%)was obtained as a fraction at a temperature of 77 to 80° C. under apressure of 2 mm Hg (260 Pa).

The obtained fraction was colorless transparent liquid and had thefollowing properties.

(Heat Stability and the Runaway Temperature)

A sample of the product was slowly heated in a capillary tube (a sealedtube) to 200° C. and kept at this temperature for 1 hour. Nodecomposition was observed, and the product was thermally stable. In thethermal analysis in which the temperature was raised to 400° C. at arate of 10° C. per minute using an apparatus for the TG/DTA thermalanalysis, heat generation started at 20 to 210° C., and a gradualdecrease in the weight was observed. The peak temperature of the heatgeneration was 255° C. The temperature of the start of heat generationwas 159° C. as measured in accordance with the method of measuring therunaway reaction of Japanese Industrial Standard (the ARC test) forevaluating the heat stability of a substance in the adiabatic condition.

EXAMPLE 1 Fluorination of methyl2,3-O-isopropylidene-β-D-ribo-furanoside

A 100 ml glass reactor equipped with a stirrer and a condenser andcoated with a fluororesin was used. Into the reactor, methyl2,3-O-isopropylidene-β-D-ribofuranoside (10 mmole) as the substrate,N,N-diethyl-α,α-difluoro(3-methyl)benzylamine (12 mmole; 2.56 g) as thefluorinating agent and 20 ml of heptane were placed. While the resultantmixture was stirred, the temperature was raised from the roomtemperature to 100° C., and the reaction was allowed to proceed for 60minutes. After the reaction was completed, 50 ml of water was added tothe fluid formed by the reaction, and the resultant mixture was treatedby extraction twice with 20 ml of dichloromethane. The extract was driedwith magnesium sulfate, filtered and distilled under a reduced pressure,and a product was obtained. The product was identified in accordancewith IR, NMR and the mass analysis and quantitatively analyzed inaccordance with the gas chromatography or the liquid chromatography. Theyield of methyl 2,3-O-isopropylidene-5-deoxy-5-fluoro-β-D-ribofuranosideas the product was 55%.

EXAMPLE 2 Fluorination of methyl2,3-O-isopropylidene-β-D-ribo-furanoside

In a microwave oven in which uniform irradiation can be made by adistributor of the pyramid type (the width and the depth: 55 cm; theheight: 70 cm; the output: 1 KW; the frequency: 2.45 GHz), a 100 mlglass reactor equipped with a stirrer and a condenser and coated with afluororesin was placed. Into the reactor, methyl2,3-O-isopropylidene-β-D-ribofuranoside (10 mmole; 2.04 g) as thesubstrate and N,N-diethyl-α,α-difluoro(3-methyl)benzylamine (12 mmole;2.56 g) as the fluorinating agent were placed. While the resultantmixture was stirred at the room temperature, the mixture was irradiatedwith microwave for 10 minutes. After the irradiation was completed, thesame treatments as those conducted in Example 1 were conducted, andmethyl 2,3-O-isopropylidene-5-deoxy-5-fluoro-β-D-ribofuranoside as theobject product was obtained at a yield of 65%. As a byproduct,2,3-O-isopropylidene-5-O-methyl-β-D-ribofuranosyl fluoride was obtainedat a yield of 20%.

COMPARATIVE EXAMPLE 1 Fluorination of methyl2,3-O-isopropylidene-β-D-ribo-furanoside

Into 20 ml of dried dichloromethane, methyl2,3-O-isopropylidene-β-D-ribofuranoside (10 mmole) as the substrate wasdissolved. While the solution was stirred under the nitrogen stream,N,N-diethylaminosulfur trifluoride (DAST, 10 mmole) was slowly addeddropwise. After the addition was completed, the reaction was allowed toproceed for 15 minutes. Water in an amount of 50 ml was poured into theobtained reaction fluid. After the resultant mixture was separated intotwo layers, the organic layer was dried with magnesium sulfate andtreated for separation in accordance with the chromatography.2,3-O-Isopropylidene-5-deoxy-β-D-furanosyl fluoride was obtained as theproduct of rearrangement at a yield of 55%. However, methyl2,3-O-isopropylidene-5-deoxy-5-fluoro-β-D-ribofuranoside of the objectcompound was not obtained at all.

EXAMPLE 3 Fluorination of ethyl2,3-O-diisopropylidene-β-D-ribo-furanoside

The same procedures as those conducted in Example 2 were conductedexcept that ethyl 2,3-O-isopropylidene-β-D-ribofuranoside (10 mmole) asthe substrate and N,N-diethyl-α,α-difluoro(3-methyl)-benzylamine (20mmole) as the fluorinating agent were used. As the products, ethyl2,3-O-isopropylidene-5-deoxy-5-fluoro-β-D-ribofuranoside was obtained ata yield of 55%, and 2,3-O-isopropylidene-5-O-ethyl-β-D-furanosylfluoride was obtained at a yield of 21%.

EXAMPLE 4 Fluorination of isopropyl2,3-O-isopropylidene-β-D-ribo-furanoside

The same procedures as those conducted in Example 3 were conductedexcept that isopropyl 2,3-O-isopropylidene-β-D-ribofuranoside (10 mmole)was used as the substrate. As the products, isopropyl2,3-O-isopropylidene-5-deoxy-5-fluoro-β-D-ribofuranoside was obtained ata yield of 62%, and 2,3-O-isopropylidene-5-O-isopropyl-β-D-furanosylfluoride was obtained at a yield of 22%.

EXAMPLE 5 Fluorination of 2′,3′-O-isopropylideneuridine

The same procedures as those conducted in Example 3 were conductedexcept that 2′,3′-O-isopropylideneuridine (10 mmole) was used as thesubstrate. As the product,2′,3′-O-isopropylidene-5′-deoxy-5′-fluorouridine was obtained at a yieldof 55%.

EXAMPLE 6 Fluorination of1,2,3,4-di-O-isopropylidene-α-D-galacto-pyranose

The same procedures as those conducted in Example 3 were conductedexcept that N,N-diethyl-α,α-difluoro(3-methyl)benzylamine (20 mmole) wasused as the substrate. As the product,1,2,3,4-di-O-isopropylidene-6-deoxy-6-fluoro-α-D-galactopyranose wasobtained at a yield of 75%.

EXAMPLE 7 Fluorination of α-D-ribofuranose 1,3,5-tribenzoate

Into a pressure resistant vessel (200 ml) of the closed type which wasmade of Teflon and attached with a fiber optic temperature sensor, astirrer rod, α-D-ribofuranose 1,3,5-tribenzoate (11 mmole; 5.1 g) and 50ml of acetonitrile were placed. To the resultant mixture,N,N-diethyl-α,α-difluoro(3-methyl)benzylamine (23.2 mmole; 49.5 g) wasslowly added under a nitrogen atmosphere. The temperature was thenraised to 200° C. at a rate of 20° C./min under stirring, and thereaction was allowed to proceed for 20 minutes. After the reaction wascompleted, the reaction product was poured into 200 ml of ice water, andthe organic layer was separated. The aqueous layer was treated byextraction with 50 ml of acetonitrile. The obtained two organic layerswere combined, washed with pure water, dried with magnesium sulfate andthen filtered. The obtained organic solution was concentrated using anevaporator, and the concentrated solution was analyzed in accordancewith the liquid chromatography. As the result, 2.8 g (the yield: 55%) of2-deoxy-2-fluoro-α-D-ribofuranose 1,3,5-tribenzoate of the objectcompound was obtained.

EXAMPLE 8 Fluorination of 2,3,5,6-di-O-isopropylidene-D-mannofuranose

The same procedures as those conducted in Example 1 were conductedexcept that 2,3,5,6-di-O-isopropylidene-D-mannofuranose (10 mmole) wasused as the substrate, and the reaction was allowed to proceed at theroom temperature for 1 hour. As the product,2,3,5,6-diisopropylidene-D-mannofuranosyl fluoride was obtained at ayield of 94% without removal of the acetonide of the protective group atall.

COMPARATIVE EXAMPLE 2 Fluorination of2,3,5,6-di-O-isopropylidene-D-mannofuranose

The same procedures as those conducted in Example 8 were conductedexcept that HF (20 mmoles) was used as the fluorinating agent. As theresult, the protective group was removed, and2,3,5,6-di-O-isopropylidene-D-mannofuranosyl fluoride of the objectcompound was not obtained at all. The fluorination at the 1-positioncould not be achieved.

EXAMPLE 9 Fluorination of 2,3,4,5-tetra-O-acetyl-D-glucopyranose

The same procedures as those conducted in Example 1 were conductedexcept that 2,3,4,5-tetra-O-acetyl-D-glucopyranose (10 mmole) was usedas the substrate, and the reaction was allowed to proceed at the roomtemperature for 1 hour in methylene chloride. As the product,2,3,4,5-tetra-O-acetyl-D-glucopyranosyl fluoride was obtained at a yieldof 84% without removal of the acetyl group of the protective group atall.

COMPARATIVE EXAMPLE 3 Fluorination of2,3,4,5-tetra-O-acetyl-D-glucopyranose

The same procedures as those conducted in Example 9 were conductedexcept that HF (20 mmoles) was used as the fluorinating agent. As theresult, the protective group was removed, and2,3,4,5-tetra-O-acetyl-D-glucopyranosyl fluoride of the object compoundwas not obtained. The fluorination at the 1-position could not beachieved.

EXAMPLE 10 Fluorination of 2,3,4,5-tetra-O-acetyl-D-glucopyranose

The same procedures as those conducted in Example 2 were conductedexcept that 2,3,4,5-tetra-O-acetyl-D-glucopyranose (10 mmole) was usedas the substrate. As the product,2,3,4,5-tetra-O-acetyl-D-glucopyranosyl fluoride was obtained at a yieldof 84% without removal of the acetyl group of the protective group atall.

EXAMPLE 11 Fluorination of α-D-ribofuranose 1,3,5-tribenzoate

The same procedures as those conducted in Example 7 were conductedexcept that α-D-ribofuranose 1,3,5-tribenzoate (11 mmole) was used asthe substrate, N,N-diethyl-α,α-difluoro(2-methoxy)benzylamine (23.2mmole) was used as the fluorinating agent, and the reaction was allowedto proceed at 120° C. for 30 minutes. As the product,2-deoxy-2-fluoro-α-D-robofuranose 1,3,5-tribenzoate was obtained at ayield of 85%.

EXAMPLE 12 Fluorination of D-xylopyranose

The same procedures as those conducted in Example 9 were conductedexcept that D-xylopyranose (10 mmole) was used as the substrate, and afluorination agent (80 mmole) was used. As the product,2,3,4-tri-O-(3′-methylbenzoyl)-D-xylopyranosyl fluoride was obtained ata yield of 57%.

EXAMPLE 13 Fluorination of1,2,3,4-di-O-isopropylidene-α-D-galactopyranose

The same procedures as those conducted in Example 6 were conductedexcept that N,N-diethyl-α,α-difluoro(2-methoxy)benzylamine (20 mmole)was used as the fluorinating agent, and the reaction was allowed toproceed at 120° C. for 48 hours without the irradiation with microwave.As the product,1,2,3,4-di-O-isopropylidene-6-deoxy-6-fluoro-α-D-galactopyranosylfluoride was obtained at a yield of 58%.

B. Using the Fluorinating Agent Represented by General Formula (III)

<Fluorination of a Primary Alcohol>

EXAMPLE 14 1-Dodecanol

In a microwave oven in which uniform irradiation can be made by adistributor of the pyramid type (the width and the depth: 55 cm; theheight: 70 cm; the output: 1 KW; the frequency: 2.45 GHz), a 100 mlglass reactor equipped with a stirrer and a condenser and coated with afluororesin was placed. Into the reactor, 1-dodecanol (10 mmole; 1.86 g)as the substrate and N,N-diethyl-α,α-difluoro(3-methyl)benzylamine (12mmole; 2.25 g) as the fluorinating agent were placed. While theresultant mixture was stirred at the room temperature, the mixture wasirradiated with microwave for 10 minutes. After the irradiation withmicrowave was completed, 50 ml of water was added to the fluid formed bythe reaction, and the resultant mixture was treated by extraction twicewith 20 ml of dichloromethane. The extract was dried with magnesiumsulfate, filtered and distilled under a reduced temperature, and aproduct was obtained. The product was identified in accordance with IR,NMR and the mass analysis and quantitatively analyzed in accordance withthe gas chromatography or the liquid chromatography. The yield of1-fluorododecane as the product was found to be 93%.

COMPARATIVE EXAMPLE 4 1-Dodecanol

The reaction was conducted in accordance with the same procedures asthose conducted in Example 14 except that the irradiation with microwavewas not conducted. The yield of 1-fluorododecane was 45% when thereaction was allowed to proceed at a temperature of 110° C. for 10minutes and 12% when the reaction was allowed to proceed at the roomtemperature for 17 hours.

EXAMPLE 15 10-Undecene-1-ol

In the same apparatus as that used in Example 14, 10-undecene-1-ol (10mmole; 1.7 g) as the substrate andN,N-diethyl-α,α-difluoro(3-methyl)benzylamine (12 mmole; 2.56 g) as thefluorinating agent were added to heptane as the solvent. While theresultant mixture was stirred at the room temperature, the mixture wasirradiated with microwave for 10 minutes. As the product,1-fluoro-10-undecene was obtained at a yield of 91%.

EXAMPLE 16 Ethylene Glycol

The reaction was conducted in accordance with the same procedures asthose conducted in Example 15 except that ethylene glycol (10 mmole) wasused, and n-heptane of the solvent was not used. One of the two hydroxylgroups in ethylene glycol alone was fluorinated after the irradiationwith microwave for 10 minutes. As the product,2-((3-methyl)benzoyloxy)-1-fluoroethane was obtained at a yield of 83%.

<Fluorination of a Secondary Alcohol>

EXAMPLE 17 cis-Cyclohexane-1,2-diol

The reaction was conducted in accordance with the same procedures asthose conducted in Example 16 except that cis-cyclohexane-1,2-diol (10mmole) was used as the substrate. As the product,(trans)-1-fluoro-2-((3-methyl)benzoyloxy)cyclohexane was obtained at ayield of 89%.

EXAMPLE 18 Cyclododecanol

The reaction was conducted in accordance with the same procedures asthose conducted in Example 16 except that cyclododecanol (10 mmole) wasused as the substrate. As the product, fluorocyclododecane andcyclododecene were obtained at yields of 16% and 84%, respectively.

<Fluorination of a Tertiary Hydroxyl Group>

EXAMPLE 19 Methyl α-hydroxyisobutyrate

The reaction was conducted in accordance with the same procedures asthose conducted in Example 16 except that methyl α-hydroxyisobutyrate(10 mmole) was used as the substrate. As the product, methylα-fluoroisobutyrate was obtained at a yield of 93%.

COMPARATIVE EXAMPLE 5 Methyl α-hydroxyisobutyrate

A 100 ml glass reactor equipped with a stirrer and a condenser andcoated with a fluororesin was used. Into the reactor, methylα-hydroxyisobutyrate (10 mmole) as the substrate,N,N-diethyl-α,α-difluoro(3-methyl)benzylamine (12 mmole; 2.56 g) as thefluorinating agent and 20 ml of n-heptane as the solvent were placed.The reaction was allowed to proceed at 20° C. for 5 hours understirring. The yield of methyl α-fluoroisobutyrate was 80%.

EXAMPLE 20 1-Adamantanol

The reaction was conducted in accordance with the same procedures asthose conducted in Example 16 except that 1-adamantanol (10 mmole) wasused as the substrate. As the product, 1-fluoro-adamantane was obtainedat a yield of 96%.

COMPARATIVE EXAMPLE 6 1-Adamantanol

The reaction was conducted in accordance with the same procedures asthose conducted in Comparative Example 4 using the same apparatus asthat used in Comparative Example 4 except that 1-adamantanol (10 mmole)was used as the substrate. As the product obtained after the reaction at20° C. for 5 hours under stirring, 1-fluoroadamantanol was obtained at ayield of 68%.

<Fluorination of an Epoxy Compound>

EXAMPLE 21 2-(n-Decyl)oxirane

The reaction was conducted in accordance with the same procedures asthose conducted in Example 16 except that 2-(n-decyl)oxirane (10 mmole)was used as the substrate, dodecane was used as the solvent, and theirradiation with microwave was conducted for 30 minutes. As the product,1,2-difluorododecane, i.e., a compound obtained by introduction of twofluorine atoms, was obtained at a yield of 65%.

<Fluorination of a Carbonyl Compound>

EXAMPLE 22 Benzaldehyde

The reaction was conducted in accordance with the same procedures asthose conducted in Example 16 except that benzaldehyde (10 mmole) wasused as the substrate. The yield of difluoromethylbenzene as the productwas 86%.

EXAMPLE 23 Cyclohexanone

The reaction was conducted in accordance with the same procedures asthose conducted in Example 16 except that cyclohexanone (10 mmole) wasused as the substrate. As the products, difluorocyclohexane (the yield:32%) and fluorocyclohexene (the yield: 58%) were obtained.

EXAMPLE 24 Benzoic Acid

The reaction was conducted in accordance with the same procedures asthose conducted in Example 16 except that benzoic acid (10 mmole) wasused as the substrate. The yield of benzoyl fluoride as the product was99%.

COMPARATIVE EXAMPLE 7 Cyclohexanone

Using cyclohexanone (10 mmole) as the substrate and 10 mmole of1,3-dimethyl-2,2-difluoroimidazolidine (DFI; manufactured by MITSUIKAGAKU KOGYO Co., Ltd.) as the fluorinating agent, the irradiation withmicrowave was conducted in accordance with the same procedures as thoseconducted in Example 16. However, a runaway reaction startedimmediately, and the reaction was stopped due to the danger. No objectcompound was obtained at all.

C. Using a Complex Compound of HF and a Base as the Fluorinating Agent

EXAMPLE 25

In a microwave oven in which uniform irradiation can be made by adistributor of the pyramid type (the width and the depth: 55 cm; theheight: 70 cm; the output: 1 KW; the frequency: 2.46 GHz), a 5 mlreactor made of a fluororesin (PFA) and equipped with a reflux condenserwas placed, and the fluorination was conducted.

Into the reactor, cyclohexene oxide (1 mmole; 0.1 g) as the substrateand triethylamine-3HF (0.6 mmole; 0.1 g) as the fluorinating agent wereplaced, and the resultant mixture was irradiated with microwave for 2minutes without stirring. After the irradiation with microwave wascompleted, the fluid formed by the reaction was cooled to the roomtemperature, poured into 15 ml of water and treated by extraction twicewith 15 ml of diethyl ether. The extract was neutralized with an aqueoussolution of sodium hydrogencarbonate and dried by adding a suitableamount of anhydrous potassium carbonate. After the solvent was removedby distillation under a reduced pressure, the obtained product waspurified in accordance with the column chromatography (hexane:Et₂O=1:1).As the product, trans-2-fluorocyclohexanol was obtained at a yield of71% (the purity: 98% or greater).

COMPARATIVE EXAMPLE 8

The same procedures as those conducted in Example 25 were conductedexcept that the irradiation with microwave was not conducted, and thereaction was allowed to proceed at a temperature of 115° C. for 4 hours.The yield of trans-2-fluorocyclohexanol as the product was 61%.

EXAMPLE 26

Using the same apparatus as that used in Example 25, the same proceduresas those conducted in Example 25 were conducted except thatcyclododecene oxide (1 mole; 0.17 g; the ratio of the isomers=31:69) andEt₃N-3HF (0.6 moles; 0.1 g) were used, and the irradiation withmicrowave was conducted for 10 minutes. As the product,2-fluorocyclododecanol was obtained at a yield of 76%.

COMPARATIVE EXAMPLE 9

The same procedures as those conducted in Example 26 were conductedexcept that the irradiation with microwave was not conducted, and thereaction was allowed to proceed at a temperature of 155° C. for 4 hours.The yield of 2-fluorocyclododecanol as the product was 54%.

EXAMPLE 27

Using the same apparatus as that used in Example 25, the same proceduresas those conducted in Example 25 were conducted except that cycloocteneoxide (1 mole) and Et₃N-3HF (1 mole) were used, and the irradiation withmicrowave was conducted for 10 minutes. As the product,trans-2-fluorocyclohexanol was obtained at a yield of 68%.

COMPARATIVE EXAMPLE 10

The same procedures as those conducted in Example 27 were conductedexcept that the irradiation with microwave was not conducted. The yieldof trans-2-fluorocyclooctanol as the product was 54%.

EXAMPLE 28

The same procedures as those conducted in Example 25 were conductedexcept that cyclododecane-1,4,8-triene monoxide (1 mole) as thesubstrate and Et₃N-3HF (1 mole) were used, and the irradiation withmicrowave was conducted for 2 minutes. As the product,2-fluorocyclododecane-6,10-diene-1-ol was obtained at a yield of 78%.

COMPARATIVE EXAMPLE 11

The same procedures as those conducted in Example 28 were conductedexcept that the irradiation with microwave was not conducted, and thereaction was allowed to proceed at a temperature of 155° C. for 4 hours.The yield of 2-fluorocyclododecane-6,10-diene-1-ol as the product was51%.

EXAMPLES 29 TO 36 AND COMPARATIVE EXAMPLES 12 TO 19

Using the same apparatus as that used in Example 25, the fluorinationunder irradiation with microwave (Examples) and the fluorination inaccordance with the thermal reaction (Comparative Examples) werecompared using the substrates and the fluorinating agents shown inTable 1. The results are shown in Table 1.

EXAMPLE 37

The same procedures as those conducted in Example 25 were conductedexcept that 3-phenylpropyl methyl sulfonate (1 mmole) and Et₃N-3HF (1.2mmole) were placed in a 10 ml reactor made of PFA, and the irradiationwith microwave was conducted for 2 minutes. As the product,1-fluoro-3-phenylpropane was obtained at a yield of 80%.

COMPARATIVE EXAMPLE 20

The reaction was conducted in accordance with the same procedures asthose conducted in Example 37 except that the reaction of 3-phenylpropylmethyl sulfonate (1 mmole) and Et₃N-3HF (10 mmole) was allowed toproceed at 80° C. for 100 hours in an acetonitrile solvent, and theyield of the product was examined. The change in the yield of1-fluoro-3-methylpropane with time was as follows: The yield after 10hours: 12% The yield after 20 hours: 20% The yield after 38 hours: 44%The yield after 54 hours: 74% The yield after 79 hours: 80% The yieldafter 100 hours: 80%

TABLE 1 (Reaction): substrate to product Example and Fluorinating agentTemperature Time Yield Comparative Example (reaction agent) (° C.) (min)(%) (Hydrofluorination): 2,3-dimethyl-2-butene to2-fluoro-2,3-dimethylbutane Example 29 triethylamine-3HF room temp. 5 77Comparative Example 12 triethylamine-3HF 100 60 72 (Halofluorination):cyclododecene to 1-bromo-2-fluorododecane Example 30 triethylamine-3HF(NBS) room temp. 5 98 Comparative Example 13 triethylamine-3HF (NBS)room temp. 60 95 (Halogen-fluorine exchange):2,4,6-trichloro-5-methylpyrimidine to 2,4,6-trifluoro-5-methylpyrimidineExample 31 triethylamine-3HF room temp. 5 94 Comparative Example 14triethylamine-3HF 60 360 91 (Fluorination with removal of diazo group):benzene diazoniumtetrafluoroborate to fluorobenzene Example 32triethylamine-3HF room temp. 10 96 Comparative Example 15triethylamine-3HF 40 480 76 (Removal of protective group of a silylether): 1,3-butanediol 1-t-butyldiphenylsiyl ether to 1,3-butanediolExample 33 triethylamine-3HF room temp. 5 89 Comparative Example 16triethylamine-3HF 80 480 82 (Reductive fluorination): 2-adamantane to2-fluoroadamantane Example 34 pyridine-3HF (triethylsilane) room temp. 578 Comparative Example 17 pyridine-3HF (triethylsilane) 60 60 68(Fluorination of saccharide): β-D-glucopyranosyl bromide tetraacetate toβ-D-glucopyranosyl fluoride tetraacetate Example 35 triethylamine-3HFroom temp. 5 84 Comparative Example 18 triethylamine-3HF 60 120 68(Fluorination of saccharide): β-D-glucopyranosyl tetraacetate toβ-D-glucopyranosilyl fluoride triacetate Example 36 triethylamine-3HFroom temp. 10 61 Comparative Example 19 triethylamine-3HF room temp. 1800

INDUSTRIAL APPLICABILITY

In accordance with the present invention, the fluorination of varioussubstrates which are hardly fluorinated in accordance with theconventional technology can proceed highly selectively, efficiently in ashort time and safely. The substrates are, for example, saccharidesuseful as the functional chemical such as materials for drugs, cosmeticsand healthy foods, compounds having hydrogen atom activated by asubstituent at the α position, the β-position or the γ-position, silylether compounds, compounds having an unsaturated group, hydroxyl group,a halogeno group, amino group, diazo group, triazeno group or isocyanogroup as the functional group, and cyclic compounds havingthree-membered or greater ring which may have heteroatoms.

1. A method of fluorination which comprises fluorinating a saccharideusing a fluorinating agent represented by general formula (I):

wherein Y represents nitrogen atom or phosphorus atom, R⁰, R¹ and R²represent hydrogen atom or an alkyl or aryl group which may havesubstituents, the atom and the groups represented by R⁰, R¹ and R² maybe a same with or different from each other and two or three of thegroups represented by R⁰, R¹ and R² may be bonded to each other to forma ring.
 2. A method of fluorination according to claim 1, wherein, ingeneral formula (I), Y represents nitrogen atom, R⁰ represents3-methyphenyl group or 2-methoxyphenyl group, and R¹ and R² representethyl group.
 3. A method of fluorination according to claim 1, whereinthe saccharide is fluorinated by a thermal reaction.
 4. A method offluorination which comprises fluorinating a substrate by bringing thesubstrate and a fluorinating agent into reaction with each other underirradiation with at least one of microwave and electromagnetic wavehaving a wavelength around a microwave region.
 5. A method offluorination according to claim 4, wherein the substrate is fluorinatedby bringing the substrate and the fluorinating agent into reaction witheach other under irradiation with microwave having a frequency of 1 to30 GHz.
 6. A method of fluorination according to claim 4, wherein thefluorinating agent is a compound represented by general formula (II):

wherein Y represents nitrogen atom or phosphorus atom, X representshydrogen atom or a halogen atom, R⁰, R¹ and R² represent hydrogen atomor an alkyl or aryl group which may have substituents, the atom and thegroups represented by R⁰, R¹ and R² may be a same with or different fromeach other, and two or three of the groups represented by R⁰, R¹ and R²may be bonded to each other to form a ring.
 7. A method of fluorinationaccording to claim 6, wherein the fluorinating agent is a compoundrepresented by general formula (III):

wherein R³, R⁴ and R⁵ each independently represent an alkyl or arylgroup which may have substituents, X represents hydrogen atom or ahalogen atom, and two or three of the groups represented by R³, R⁴ andR⁵ may be bonded to each other to form a cyclic structure.
 8. A methodof fluorination according to claim 7, wherein, in general formula (III),R³ represents an aryl group which may have substituents, X representsfluorine atom, and R⁴ and R⁵ represent an alkyl or aryl group having 1to 32 carbon atoms which may have substituents.
 9. A method offluorination according to claim 6, wherein the substrate is an organiccompound having at least one atom selected from the group consisting ofoxygen atom, nitrogen atom and sulfur atom.
 10. A method of fluorinationaccording to claim 9, wherein the substrate is a compound havinghydroxyl group.
 11. A method of fluorination according to claim 10,wherein the substrate is a diol having hydroxyl groups adjacent to eachother.
 12. A method of fluorination according to claim 10, wherein thesubstrate is a saccharide.
 13. A method of fluorination according toclaim 12, wherein the fluorinating agent is a compound represented bygeneral formula (II) in which X represents fluorine atom.
 14. A methodof fluorination according to claim 13, wherein the fluorinating agent isa compound represented by general formula (II) in which X representsfluorine atom, Y represents nitrogen atom, R⁰ represents 3-methylphenylgroup or 2-methoxyphenyl group, and R¹ and R² represent ethyl group. 15.A method of fluorination according to claim 12, wherein the saccharideis a compound selected from the group consisting of monosaccharides,glycosides, anhydrides of monosaccharides, oligosaccharides andpolysaccharides.
 16. A method of fluorination according to claim 9,wherein the substrate is a compound having carbonyl group or carboxylgroup.
 17. A method of fluorination according to claim 9, wherein thesubstrate is an epoxide.
 18. A method of fluorination according to claim4, wherein the fluorinating agent is a complex compound comprising HFand a base.
 19. A method of fluorination according to claim 18, whereinthe fluorinating agent is an alkylamine-HF complex compound.
 20. Amethod of fluorination according to claim 19, wherein the fluorinatingagent is a triethylamine-HF complex compound.
 21. A method offluorination according to claim 18, wherein the fluorination isconducted in a presence of an agent accelerating a reaction.
 22. Amethod of fluorination according to claim 18, wherein the substrate is acompound having hydrogen atom activated by a substituent at an αposition, a β-position or a γ-position, a silyl ether compound, acompound having an unsaturated group, hydroxyl group, a halogeno group,amino group, diazo group, triazeno group or isocyano group as afunctional group, or a cyclic compound having three-membered or greaterring which may have heteroatoms.
 23. A method of fluorination accordingto claim 18, wherein the substrate is a saccharide or a cyclic compoundhaving cyclopropane ring, oxirane ring, aziridine ring or 1,3-dithianering.
 24. A method of fluorination according to claim 5, wherein thefluorinating agent is a compound represented by general formula (II):

wherein Y represents nitrogen atom or phosphorus atom, X representshydrogen atom or a halogen atom, R⁰, R¹ and R² represent hydrogen atomor an alkyl or aryl group which may have substituents, the atom and thegroups represented by R⁰, R¹ and R² may be a same with or different fromeach other, and two or three of the groups represented by R⁰, R¹ and R²may be bonded to each other to form a ring.